International patent applications including WO 03/029232 and WO 2007/144005 disclose the compound 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine and pharmaceutically acceptable salts thereof. WHO has since published that vortioxetine is the recommended International Non-proprietary Name (INN) for 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine. Vortioxetine was formerly referred to in the literature as Lu AA21004. FDA and EMA have since approved vortioxetine for the treatment of depression under the trade name Brintellix™.
Vortioxetine is a 5-HT3, 5-HT7, and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of the 5-HT transporter. Additionally, vortioxetine has demonstrated to enhance the levels of the neurotransmitters serotonin, noradrenalin, dopamine, acetylcholine and histamine in specific areas of the brain. All of these activities are considered to be of clinical relevance and potentially involved in the mechanism of action of the compound [J. Med. Chem., 54, 3206-3221, 2011; Eur. Neuropshycopharmacol., 18(suppl 4), S321, 2008; Eur. Neuropshycopharmacol., 21(suppl 4), S407-408, 2011; Int. J. Psychiatry Clin Pract. 5, 47, 2012].
Vortioxetine has in clinical trials shown to be a safe and efficacious treatment for depression. A paper reporting the results from a proof-of-concept study to evaluate the efficacy and tolerability of the compound in patients with major depressive disorder (MDD) authored by Alvares et at was made available on-line by Int. J. Neuropsychopharm. 18 Jul. 2011. The results from the six weeks, randomised, placebo-controlled study with approximately 100 patients in each arm show that vortioxetine separates significantly from placebo in the treatment of depressive and anxious symptoms in patients with MDD. It is also reported that no clinically relevant changes were seen in the clinical laboratory results, vital signs, weight, or ECG parameters. Results from a long-term study also show that vortioxetine is effective in preventing relapse in patients suffering from MDD [Eur. Neuropsychopharmacol. 21(suppl 3), S396-397, 2011]. A study in elderly depressed patients reported in Int. Clin. Psychopharm., 27, 215-227, 2012 shows that vortioxetine may be used to treat cognitive dysfunctions.
The manufacturing process used to prepare vortioxetine disclosed in WO 03/029232 is based on solid-phase synthesis and exploits di-arene iron-assisted nucleophilic aromatic substitution reactions in a multistep process. In summary, 4-[piperazine-1-yl]carbonyloxymethyl]phenoxymethyl polystyrene was reacted with a di-arene iron salt, i.e. η6-1,2-dichlorobenzene-η5-cyclopentadienyliron(II) hexafluorophosphate followed by isolation and washing of the resin and further reaction with 2,4-dimethylthiophenol. Finally, the thus obtained resin was treated with 1,10-phenanthroline and light to de-complex cyclopentadienyliron. The overall yield was low, only 17%. A similar process is disclosed in WO 01/49678 wherein phenoxyphenylpiperazines are prepared as intermediates.
Di-arene iron compounds have been known for long time, exemplified by ferrocene which consists of two pentadienyl rings bound to iron in a sandwich structure. These compounds have proved to be useful tools in the preparation of e.g. heterocyclic compounds. As an example, Pearson et al in J. Org. Chem. 61, 1297-1305, 1996 disclose displacement of chloro atoms from 1,4-dichlorobenzene-cyclopentadienyl-iron (II) by cyclic secondary amines, e.g. piperazine. Interestingly, this reaction results in a symmetric displacement, i.e. displacement of both chloro atoms from the benzene moiety. Sutherland et al in J. Heterocyclic Chem., 19, 801-803, 1982 disclose that both chloro atoms in 1,2-dichlorobenzene-cyclopentadienyl-iron(II) are displaced by substituted 1,2-dithiophenol to obtain the corresponding thiaanthrenes. Pearson et al [J. Org Chem., 59, 4561-4570, 1994] disclose the use of 1-4-dichlorobenzene-cyclopentadienyl-iron(II)hexafluorophosphate in the manufacture of asymmetric compounds in which the two chloro atoms are substituted by phenoxy and morpholine, respectively. Notably, the two substitutions require very different reaction conditions and isolation of the intermediate, mono-substituted compound was required. Ruhland et al in J. Org. Chem., 67, 5257-5268, 2002 disclose synthesis of 1,2-disubstituted benzenes where selective substitution with different substitutions of the chemically identical chloro atoms is achieved via cyclopentadienyl activation in solid phase.
Solid-phase chemistry is not feasible for pharmaceutical production involving manufacturing in ton-scale. The massive handling of resins that would be required and the costs associated are prohibitive. Additionally, the low yield obtained for votioxetine (only 17%) makes this manufacturing route unattractive.
Large scale manufacturing of vortioxetine has been disclosed in WO 2007/144005 and WO 2010/094285. Piperazine, 2,4-dimethylthiophenol and 1,2-dihalogenbenzene are mixed e.g. in toluene together with a palladium catalyst to afford vortioxetine. Although this reaction provides high yield and can be handled in large scale, it requires the use of an expensive catalyst, i.e. palladium. Moreover, the reaction conditions are harsh employing elevated temperatures to obtain a satisfactory result, i.e. reflux temperatures or 80-120° C. and the use of strong base.
The present invention provides a manufacturing process for vortioxetine which uses inexpensive starting materials, which can be run at mild conditions and which gives high yields.